Protein kinase R is an innate immune sensor of proteotoxic stress via accumulation of cytoplasmic IL-24.
Sophia DavidsonChien-Hsiung YuAnnemarie SteinerFrédéric EbsteinPaul J BakerValentina Jarur-ChamyKatja Hrovat-SchaalePawat LaohamonthonkulKlara KongDale J CallejaCassandra R HarapasKatherine R BalkaJacob T MitchellJacob T JacksonNiall D GeogheganFiona MoghaddasKelly L RogersKatrin D Mayer-BarberAdriana Almeida de JesusDominic De NardoBenjamin T KileAnthony J SadlerMaria Cecilia PoliElke KrügerRaphaela Goldbach ManskySeth L MastersPublished in: Science immunology (2022)
Proteasome dysfunction can lead to autoinflammatory disease associated with elevated type I interferon (IFN-αβ) and NF-κB signaling; however, the innate immune pathway driving this is currently unknown. Here, we identified protein kinase R (PKR) as an innate immune sensor for proteotoxic stress. PKR activation was observed in cellular models of decreased proteasome function and in multiple cell types from patients with proteasome-associated autoinflammatory disease (PRAAS). Furthermore, genetic deletion or small-molecule inhibition of PKR in vitro ameliorated inflammation driven by proteasome deficiency. In vivo, proteasome inhibitor-induced inflammatory gene transcription was blunted in PKR-deficient mice compared with littermate controls. PKR also acted as a rheostat for proteotoxic stress by triggering phosphorylation of eIF2α, which can prevent the translation of new proteins to restore homeostasis. Although traditionally known as a sensor of RNA, under conditions of proteasome dysfunction, PKR sensed the cytoplasmic accumulation of a known interactor, interleukin-24 (IL-24). When misfolded IL-24 egress into the cytosol was blocked by inhibition of the endoplasmic reticulum-associated degradation pathway, PKR activation and subsequent inflammatory signaling were blunted. Cytokines such as IL-24 are normally secreted from cells; therefore, cytoplasmic accumulation of IL-24 represents an internal danger-associated molecular pattern. Thus, we have identified a mechanism by which proteotoxic stress is detected, causing inflammation observed in the disease PRAAS.
Keyphrases
- innate immune
- oxidative stress
- protein kinase
- small molecule
- induced apoptosis
- endoplasmic reticulum
- diabetic rats
- dendritic cells
- single cell
- signaling pathway
- genome wide
- immune response
- cell therapy
- transcription factor
- stem cells
- gene expression
- copy number
- heat stress
- cell death
- cell cycle arrest
- inflammatory response
- dna methylation
- pi k akt
- endothelial cells
- genome wide identification